Selectively permeable membranes have been used to encapsulate cells which secrete biologically-active factors useful for the treatment of various diseases and disorders. Typically, the cells are loaded into the membranes which are in the form of hollow fibers or between two flatsheets in the form of a sandwich. The fibers are then sealed at the ends to form "macrocapsules". The encapsulated cells are implanted into a patient in need of the biologically-active factors produced by the cells. Macrocapsules offer the advantage of easy retrievability, an important feature in therapeutic implants.
An example of macrocapsules can be found in U.S. Pat. No. 4,892,538, which describes the encapsulation of neurotransmitter-secreting cells which are implanted into a patient having a neurotransmitter-deficiency disease.
U.S. Pat. No. 5,158,881 also discloses methods and systems for encapsulating cells which produce biologically-active factors. The cells are encapsulated with a semipermeable polymeric membrane by co-extruding an aqueous cell suspension and a polymeric solution through a common port to form a tubular extrudate having a polymeric outer coating which encapsulates the cell suspension. Cells can also be loaded into pre-formed hollow fiber membranes.
Typically, the semipermeable membranes used to encapsulate cells are formed from polymeric materials such as acrylic copolymers, polyvinylidene fluoride, polyurethane isocyanates, polyalginate, cellulose acetate, polysulfone, polyvinyl alcohols, polyacrylonitrile and mixtures or derivatives thereof. Poly(acrylonitrile-co-vinyl chloride) (PAN/PVC) is one of the polymers used to make implantable membranes because it can easily be made into permselective membranes that allow easy transport of nutrients and greatly reduce transport of immuno-molecules. These membranes can be made with a wide variety of wall thicknesses and morphologies. PAN/PVC is moderately hydrophilic and is non-toxic to cells.
While these materials have the capability of being formed into permeable-selective, biocompatible membranes, there exists the need to further improve the characteristics of the membranes to increase their utility for macroencapsulation purposes. One shortcoming of some polymeric membranes is that proteins secreted from the encapsulated cells and proteins from the patient, tend to adsorb to them, thus decreasing the diffusion rate of the protein to the patient and hence the efficiency of the implant.
Various modifications have been made to polymeric materials to change their characteristics and to improve their usage for particular therapeutic applications. For example, U.S. Pat. No. 4,871,785 to Froix et al. describes hydrogel contact lens compositions which are modified to contain significant amounts of a cross-linking material such as polyethylene oxide. The modification results in a lens having decreased protein adsorption. Allmer et al. have grafted polyethylene glycol (PEG) and heparin onto polymer surfaces to inhibit protein adsorption and to prevent surface activated blood clotting [J. of Polymer Sci. Vol 28:176-183 (1990)]. Miyama et al. describe graft copolymers having improved antithrombogenicity after being heparinized [J.Biomed Mater. Res., Vol. 11:251-265 (1977)]. U.S. Pat. No. 4,424,311 to Nagaoka et al. describes an antithrombogenic biomedical material comprising a polymer having a polyethylene oxide unit. U.S. Pat. No. 4,965,112 to Brinkman et al. describes a method for applying polyethylene oxide coating to polyether-urethane molded articles such as catheters in order to improve blood-compatibility. Published PCT application PCT/US91/07051 describes grafting poly(ethylene oxide) onto microcapsules made of polycationic polymers such as poly(l-lysine). Fane et al. disclose that treating various ultrafiltration membranes with nonionic surfactants can enhance flux of protein solutions [Desalination, Vol. 53:37-55 (1985)].